Table of Contents

Volume 7, Issue 7

  April 1, 2008

  Pages 837 - 959

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 Issue Catalogue (MARC XML)

EXTRA VIEWS

Open Access Article

Guilt by association: PAX3-FOXO1 regulates gene expression through selective destabilization of the EGR1 transcription factor

Wendy Roeb, Antonia Boyer, Webster K. Cavenee and Karen C. Arden
Pages 837 - 841
http://dx.doi.org/10.4161/cc.7.7.5652
Abstract | PDF

Human cancer cells frequently harbor chromosomal translocations that create chimeric fusion genes. The t(2;13) translocation is characteristic of the pediatric muscle tumor, alveolar rhabdomyosarcoma, and produces the chimeric transcription factor, PAX3-FOXO1, that contains the DNA binding elements of PAX3 and the transcriptional activation domain of FOXO1. Experiments designed to determine how PAX3-FOXO1 expression contributes to the development of muscle cell-derived tumors resulted in the discovery that the fusion protein misregulates gene expression and interrupts myogenic differentiation through a unique gain of function mechanism. These results yield new insight into how tumor-associated genetic alterations increase the likelihood of cancer formation and may lead to new therapeutic approaches.

Open Access Article

The tumor suppressor p53: Cancer and aging

Zhaohui Feng, Wenwei Hu, Gunaretnam Rajagopal and Arnold J. Levine
Pages 842 - 847
http://dx.doi.org/10.4161/cc.7.7.5657
Abstract | PDF

Aging, like many other biological processes, is subject to regulation by genes that reside in pathways that have been conserved during evolution. The insulin/ IGF-1 pathway, mTOR pathway and p53 pathway are among those conserved pathways that impact upon longevity and aging-related diseases such as cancer. Most cancers arise in the last quarter of life span with the frequency increasing exponentially with time, and mutation accumulation in critical genes (e.g. p53) in individual cells over a lifetime is thought to be the reason. Recently, we found that the efficiency of the p53 response to stress decline significantly with age in mice, and the time of onset of this decreased p53 response correlates with the life span of mice. Given the crucial role of the p53 in tumor prevention, this decline in p53 activity at older ages in animals could contribute to the observed dramatic increases in cancer frequency, and provides a plausible explanation for the correlation between tumorigenesis and aging in addition to the accumulation of DNA mutations over lifetime. We discuss here the coordination and communication between the p53 pathway and the IGF-1-mTOR pathways, and their possible impact on cancer and longevity.

Open Access Article

p53: A new player in reproduction

Wenwei Hu, Zhaohui Feng, Gurinder S. Atwal and Arnold J. Levine
Pages 848 - 852
http://dx.doi.org/10.4161/cc.7.7.5658
Abstract | PDF

The roles of the p53 protein in tumor suppression have been firmly established. However, the functions of this protein under normal conditions or in the absence of stress, if any, have remained a mystery. In humans, some alleles containing a functional single nucleotide polymorphism in the p53 gene and its negative regulator, the Mdm2 gene, are under positive selection over evolutionary time frames, suggesting that the p53 pathway might have important functions that are optimized and selected for by evolutionary or reproductive pressures. Indeed, a recent study demonstrated a new function for the p53 protein in the regulation of maternal reproduction in mice, through transcriptional regulation of leukemia inhibitory factor (LIF), a novel p53 target gene. Sufficient uterine LIF levels are essential for the implantation of blastocysts or early embryos into the uterus. p53 deficient (p53-/-) female mice have a reduced pregnancy rate and litter size, due to impaired implantation resulting from decreased uterine LIF levels. Administration of LIF to pregnant p53-/- mice restored maternal reproduction by improving implantation. An association has been reported between women carrying the p53 codon 72 polymorphism (a proline to arginine change) with recurrent implantation failure, suggesting a similar function for p53 in humans. These findings of a new function for the p53 protein in reproduction may help to explain the observed evolutionary selection of some alleles of the p53 and Mdm2 genes. This may also be an excellent example of antagonistic pleiotrophy.

Open Access Article

MiRSNPs or MiR-polymorphisms, new players in microRNA mediated regulation of the cell: Introducing microRNA pharmacogenomics

Prasun J. Mishra, Pravin J. Mishra, Debabrata Banerjee and Joseph R. Bertino
Pages 853 - 858
http://dx.doi.org/10.4161/cc.7.7.5666
Abstract | PDF

MicroRNAs are evolutionarily conserved small non-coding RNAs known to inhibit the translation of proteins by binding to the target transcript in the 3’ untranslated region. Functional polymorphisms in 3’ UTRs of several genes have been reported to be associated with diseases by affecting gene expression. The mechanism by which these polymorphisms affect gene expression and induce variability in a cell is not well understood. It has been suggested that these polymorphisms may interfere with regulatory elements that bind to untranslated region of a gene. Recently, a novel class of functional polymorphisms termed miRSNPs/polymorphisms was reported.1, 2 defined as a polymorphism present at or near a microRNA binding sites of functional genes that can affect gene expression by interfering with a miRNA function. The work elucidated the mechanism of a functional miRSNP 829C→T present in 3’ UTR of dihydrofolate reductase, an important drug target. The SNP interferes with the miR24 microRNA function and leads to DHFR over expression and methotrexate resistance. In this article we highlight the importance of these miRSNPs or miR-polymorphisms in gene regulation and the mechanism by which these miRSNPs can induce variability in the SNP expressing mutant cell by using drug resistance as an example.




PERSPECTIVES

Open Access Article

Break-induced replication: What is it and what is it for?

Bertrand Llorente, Catherine E. Smith and Lorraine S. Symington
Pages 859 - 864
http://dx.doi.org/10.4161/cc.7.7.5613
Abstract | PDF

Homologous recombination (HR) is considered to be an error-free mechanism for the repair of DNA double-strand breaks (DSBs). Indeed, most DSB repair events occur by a non-crossover mechanism limiting loss of heterozygosity (LOH) for markers downstream of the site of repair and preventing chromosome rearrangements. However, DSBs that arise by replication fork collapse or by erosion of uncapped telomeres have only one free end and are thought to repair by strand invasion into a homologous duplex DNA followed by replication to the chromosome end (break-induced replication, BIR). As BIR from one of the two ends of a DSB would result in a long tract of LOH it suggests BIR is suppressed when DSBs have two ends in order for repair to occur by a more conservative HR mechanism. Recent studies showed that BIR can occur by several rounds of strand invasion, DNA synthesis and dissociation resulting in chromosome rearrangements when dissociation and reinvasion occur within dispersed repeated sequences. Thus template switching BIR can be highly mutagenic and this process could be important for genome evolution and disease development in humans.

Open Access Article

Untangling the unfolded protein response

Emma L. Davenport, Gareth J. Morgan and Faith E. Davies
Pages 865 - 869
http://dx.doi.org/10.4161/cc.7.7.5615
Abstract | PDF

Resistance to current cancer therapies has forced scientists to investigate new avenues of therapy distinct from those aimed at single targets, to strategies based on targeting families of proteins, on which cancers rely for their ability to survive stress. Two such protein families are the heat shock proteins (HSP), especially the HSP90 family, and proteins involved in mediating the unfolded protein response (UPR). HSP90 stabilises key survival factors in cancer cells including AKT, ERB2 and HIF1α, which alone makes HSP90 inhibitors extremely interesting as potential therapies. In addition targeting HSP90 can destabilise the UPR inducing cell death. A broad range of cancer-types rely on the UPR to correctly fold key signalling proteins properly, as well as to allow the cell to cope with the hypoxic environment associated with tumour development. These associations suggest that a range of tumours may be targeted using HSP90 inhibitors and that the development of specific inhibitors of the UPR may be of interest. In this article, based on work in multiple myeloma, we highlight the importance of targeting multiple signalling pathways simultaneously, using the UPR and heat shock proteins as examples, as a means of effectively killing cancer cells.

Open Access Article

A spoke in the wheel: Calcium spikes disrupt yeast cell cycle

Yong-Qiang Zhang and Rajini Rao
Pages 870 - 873
http://dx.doi.org/10.4161/cc.7.7.5616
Abstract | PDF

A prerequisite of calcium signaling is the maintenance of cytoplasmic free Ca2+ within a narrow, sub-micromolar range, compatible with cell viability. A variety of stress inducing agents and drugs can lead to a disruption of calcium homeostasis with ensuing toxicity. Amiodarone, an anti-arrhythmic drug with broad range microbicidal effect, has been shown to trigger a calcium burst in the yeast Saccharomyces cerevisiae. Recently, we reported that amiodarone elicits a starvation response, blocks cell cycle progression at multiple stages and represses the transcription of cell cycle genes. Here, we examine the connections between Ca²⁺-calcineurin signaling, nutrient sensing and regulation of the cell cycle.

Open Access Article

The cytoprotective Nrf2 transcription factor controls insulin receptor signaling in the regenerating liver

Tobias A. Beyer and Sabine Werner
Pages 874 - 878
http://dx.doi.org/10.4161/cc.7.7.5617
Abstract | PDF

The Nrf2 transcription factor is a crucial regulator of the cellular redox homeostasis through its capacity to induce the expression of enzymes, which detoxify reactive oxygen species, and of other antioxidant proteins. Therefore, it plays an important role in the protection from carcinogenesis induced by various insults. In addition, recent results identified a novel role of Nrf2 in tissue repair. In the liver, regeneration after partial hepatectomy was strongly delayed in the absence of Nrf2. This defect was shown to result from transient resistance to insulin and insulin-like growth factor 1 that was caused by chronic oxidative stress in hepatocytes. These results demonstrate a link between Nrf2 deficiency, oxidative stress and insulin resistance, and suggest that activation of this transcription factor could be a novel strategy to improve liver regeneration in patients with acute or chronic liver injury. In addition, it may help to alleviate oxidative stress-induced insulin resistance in the liver and potentially also in other organs.

Open Access Article

A Hippo in the ointment: MST signalling beyond the fly

David Matallanas, David Romano, Garth Hamilton, Walter Kolch and Eric O'Neill
Pages 879 - 884
http://dx.doi.org/10.4161/cc.7.7.5630
Abstract | PDF

The regulation of cell cycle and apoptosis is fundamental to the control of cell growth and organism homeostasis. Failure to efficiently regulate these processes often results in the increased cell growth observed in tumours. Accumulation of genetic lesions frequently eliminates these regulatory steps so it is imperative that multiple signalling pathways are employed to ensure that efficient control is maintained. Over the last few years a novel signalling pathway entered the limelight that prevents inappropriate activation of the cell cycle and can elicit apoptosis to limit cell numbers. Denoted the MST/hippo pathway, it is involved in regulating cell number in organism development and tumour progression. Here we aim to review the evidence for a conserved pathway from flies to mammals, and of equal importance to initiate the discussion on the additional cellular and signalling processes that have been adopted by this pathway to achieve further regulation and diversified cellular outcomes in mammals.

Open Access Article

Molecular framework underlying pluripotency

Yuin-Han Loh, Jia-Hui Ng and Huck-Hui Ng
Pages 885 - 891
http://dx.doi.org/10.4161/cc.7.7.5636
Abstract | PDF

Pluripotency is governed by the intricate interplay between genetic and epigenetic factors. Previous studies implicate Oct4, Sox2 and Nanog as core regulators of the transcriptional circuitry in pluripotent cells. The three transcriptional factors and their downstream target genes coordinately promote self-renewal and pluripotency. Significant inroads have also been made into elucidating the epigenetic mechanisms governing the exit from a self-renewal state. The recent success in reprogramming both mouse and human fibroblast cells into a pluripotent state has marked a new era in stem cell research and is pertinent to a comprehensive understanding of pluripotency. Reprogramming can be initiated by the introduction of few defined factors. However, the molecular mechanisms driving reprogramming remain largely obscure and await further investigations. Here, we explore the molecular framework governing pluripotency in the context of pluripotent ES cells and the reprogrammed iPS cells.

Open Access Article

Switching cyclin D-Cdk4 kinase activity on and off

Stacy Blain
Pages 892 - 898
http://dx.doi.org/10.4161/cc.7.7.5637
Abstract | PDF

The cyclin-cdks are master regulators of cell proliferation. These serine/threonine kinases are the motors that both start and stop the cell cycle in response to proliferative or antiproliferative signals. They phosphorylate substrates required to trigger orderly cell cycle progression, and thus their activity is tightly regulated in order to prevent inappropriate activation. One of the main interfaces between the extraceullar environment and the cell cycle machinery is the interaction of the cyclin-cdks with two families of stoichiometric cyclin kinase inhibitors (CKIs), the Ink4s and the Cip/Kips. As their name suggests, the CKIs have historically been considered negative regulators of the cyclin-cdks, responsible for rapidly and effectively turning off cyclin-cdk activity. However, the interaction of cyclin D-cdk4 with the Cip/Kip family, and with p27Kip1 in particular, appeared complex. In addition to its ability to inhibit cyclin D-cdk4, p27 appeared to be a required assembly factor for the complex, binding in a non-inhibitory mode at least some of the time. Whether p27 was a cyclin D-cdk4/6 inhibitor or not was controversial, and how it might switch between these two modes was unknown. Arguing for a two state mechanism, we have recently shown that p27 can be both a cdk4 bound-inhibitor and a bound-non-inhibitor, depending on the growth state of the cell. This perspective highlights the significance of this finding in terms of normal cell cycle progression and tumor development.




REVIEW

Open Access Article

Interplay between microRNAs and RNA-binding proteins determines developmental processes

Martijn Kedde and Reuven Agami
Pages 899 - 903
http://dx.doi.org/10.4161/cc.7.7.5644
Abstract | PDF

MicroRNAs (miRNAs) are genes involved in normal development and cancer. They inhibit gene expression by associating with 3'-Untranslated regions (3' UTRs) of messenger RNAs (mRNAs), and are thought to regulate a large proportion of protein coding genes. However, it is becoming apparent that miRNA activity is not necessarily always determined by its expression in the cell. MiRNA activity can be affected by RNA-binding proteins (RBPs). For example, the RNA-binding protein HuR associates with the 3'UTR of the CAT1 mRNA after stress, counteracting the effect of miR-122. Second, we found that the expression of an RNA-binding protein called Dead end (Dnd1) prohibits the function of several miRNAs by blocking the accessibility of target mRNAs. Dnd1 function is essential for proper development of primordial germ cells (PGCs) in zebrafish and mammals, indicating a crucial role for RBP/miRNA interplay on 3'UTRs of mRNAs in developmental decisions. In this perspective we discuss the interplay between RBPs and miRNAs in the context of germ cells and review current observations implicating RBPs in miRNA function.




BRIEF REPORT

Open Access Article

Repression of Hedgehog signal transduction in T-lineage cells increases TCR-induced activation and proliferation

Nicola J. Rowbotham, Anna L. Furmanski, Ariadne L. Hager-Theodorides, Susan E. Ross, Ekati Drakopoulou, Costas Koufaris, Susan V. Outram and Tessa Crompton
Pages 904 - 908
http://dx.doi.org/10.4161/cc.7.7.5628
Abstract | PDF

Hedgehog proteins signal for differentiation, survival and proliferation of the earliest thymocyte progenitors, but their functions at later stages of thymocyte development and in peripheral T-cell function are controversial. Here we show that repression of Hedgehog (Hh) pathway activation in T-lineage cells, by expression of a transgenic repressor form of Gli2 (Gli2δC2), increased T-cell differentiation and activation in response to TCR signalling. Expression of the Gli2δC2 transgene increased differentiation from CD4+CD8+ to single positive thymocyte, and increased peripheral T cell populations. Gli2δC2 T-cells were hyper-responsive to activation by ligation of CD3 and CD28: they expressed cell surface activation markers CD69 and CD25 more quickly, and proliferated more than wild-type T-cells. These data show that Hedgehog pathway activation in thymocytes and T-cells negatively regulates TCR-dependent differentiation and proliferation. Thus, as negative regulators of TCR-dependent events, Hh proteins provide an environmental influence on T-cell fate.




REPORTS

Open Access Article

Mice lacking both mixed-lineage kinase genes Mlk1 and Mlk2 retain a wild type phenotype

Nicolas Bisson, Michel Tremblay, Fiona Robinson, David R. Kaplan, Steven P. Trusko and Tom Moss
Pages 909 - 916
http://dx.doi.org/10.4161/cc.7.7.5610
Abstract | PDF

The mitogen-activated protein kinase kinase kinases of the mixed-lineage kinase (MLK) family have been shown to activate the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway, and to regulate the other two principal MAPK cascades, p38 and extracellular signal-regulated kinase (ERK). Although there is growing evidence for their involvement in neuronal cell death leading to neurodegenerative disorders, little in vivo data is available for the members of this family of kinases. Here, we report that the inactivation of mouse Mlk1 and Mlk2 genes. Mlk1-/- and Mlk2-/- mice were found to be viable and healthy. Surprisingly, mice carrying the compound Mlk1/Mlk2 null mutations were also found to be viable, fertile and to have a normal life span. The nervous system, testis and kidney, the major sites of MLK1 and 2 expression, all appear normal, as do other organs where these kinases were found to be more weakly expressed. Surprisingly, developmental neuronal programmed cell death, another potential target for MLK family members, was also found to be unaffected. Our results suggest that there is extensive functional redundancy between MLK1/MLK2 and the other member of the family, MLK3, which is also not required for survival in mouse.

Open Access Article

Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1, 25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling

Farnaz Jamshidi, Jing Zhang, Jonathan S. Harrison, Xuening Wang and George P. Studzinski
Pages 917 - 924
http://dx.doi.org/10.4161/cc.7.7.5620
Abstract | PDF

Differentiation therapy of cancer is being explored as a potential modality for treatment of myeloid leukemia, and derivatives of vitamin D are gaining prominence as agents for this form of therapy. Cyclooxygenase (COX) inhibitors have been reported to enhance 1,25-dihydroxyvitamin D3 (1,25D)-induced monocytic differentiation of promyeloblastic HL60 cells, but the mechanisms of this effect are not fully elucidated, and whether this potentiation can occur in other types of myeloid leukemia is not known. We found that combination treatment with 1,25D and non-specific COX inhibitors acetyl salicylic acid (ASA) or indomethacin can robustly potentiate differentiation of other types of human leukemia cells, i.e. U937, THP-1, and that ASA +/- 1,25D is effective in primary AML cultures. Increased cell differentiation is paralleled by arrest of the cells in the G1 phase of the cell cycle, and by increased phosphorylation of Raf1 and p90RSK1 proteins. However, there is no evidence that this increase in phosphorylation of Raf1 is transmitted through the ERK module of the MAPK signaling cascade. Transfection of small interfering (si) RNA to Raf1 decreased differentiation of U937 cells induced by a combination of ASA or indomethacin with 1,25D. However, phosphorylation levels of ERK1/2, though not of p90RSK, were increased when P-Raf1 levels were decreased by the siRNA, suggesting that in this system the ERK module does not function in the conventional manner. Identification of the strong antiproliferative activity of ASA/1,25D combinations associated with monocytic differentiation has implications for cancer chemoprevention in individuals who have a predisposition to myeloid leukemia.

Open Access Article

Proteasome inhibitor MG-132 modifies coxsackie and adenovirus receptor expression in colon cancer cell line lovo

Nian-Hua Zhang, Li-Bing Song, Xiao-Jun Wu, Rui-Ping Li, Mu-Sheng Zeng, Xiao-Feng Zhu, De-Sen Wan, Qiang Liu, Yi-Xin Zeng and Xiao-Shi Zhang
Pages 925 - 933
http://dx.doi.org/10.4161/cc.7.7.5621
Abstract | PDF

The efficacy of adenovirus vector-based cancer gene therapy is controversial. Its uptake by cells in many cases requires the major receptor for adenoviruses, the coxsackievirus and adenovirus receptor (CAR). Low transduction is believed to be one of the main barriers as the expression of CAR on tumor cells is frequently reduced. Increasing CAR expression on tumor cells thus offers a promising opportunity for more effective adenovirus based treatment. Expression of CAR in 62 cases of colon tumor specimens were examined with immunohistochemistry. To modify the CAR expression, the effects of proteasome inhibitor MG132 on CAR expression of colon cancer cell lines were determined by flow cytometry, RT-PCR, and western blot. To evaluate adenovirus transfer, we further used rAd.EGFP, rAd.p53, and oncolytic adenovirus to infect target cells. The CAR expression was significantly decreased in colon carcinomas, both in primary tumors and lymphonode metastasis. Though the deregulation of CAR occurred in early disease and showed no relationship with TNM stage, when primary tumors are more than 5 cm in diameter, this deregulation becomes more frequent. More importantly, proteasome inhibitor MG-132 could enhance CAR expression in colon carcinoma cell line lovo, accompanied with enhanced adenovirus transfer, target gene expression, and oncolysis. These data provide a rational basis for evaluation of CAR expression in tumors and pretreatment with CAR conditioner prior to adenovirus vector-based gene therapy.

Open Access Article

The level of oncogene H-Ras correlates with tumorigenicity and malignancy

Beicheng Sun, Yun Gao, Lei Deng, Guoqiang Li, Feng Cheng and Xuehao Wang
Pages 934 - 939
http://dx.doi.org/10.4161/cc.7.7.5622
Abstract | PDF

Normal bovine adrenocortical cells and some human fibroblasts can be transformed by SV40T and H-Ras in a Ras-dependent manner. We recently reported that high levels of Ras derived from 5’ LTR of retrovirrus can induce highly malignant and fast growing tumors, while lower levels of Ras derived from internal ribosome entry site (IRES) promotes slower tumor growth and loss of malignancy. Ras derived from CMV promoters resulted in much lower Ras levels and loss of tumor malignancy and growth. Further studies showed that the tumors formed in the presence of lower levels of Ras and dominant negative P53 (P53DD) had fewer apoptotic cells and grew faster than the tumors formed from cells with same level Ras and SV40T. Our studies suggest that low levels of Ras are insufficient to inhibit apoptosis induced by pRb inactivation. In contrast, high levels of Ras not only allow normal cells to exit senescence and form tumors, but also protect against pRb inhibition-induced cell apoptosis.

Open Access Article

Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: A possible mechanism contributing to peripheral neuropathy and cellular toxicity following proteasome inhibition

Marianne S. Poruchynsky, Dan L. Sackett, Robert W. Robey, Yvona Ward, Christina Annunziata and Tito Fojo
Pages 940 - 949
http://dx.doi.org/10.4161/cc.7.7.5625
Abstract | PDF

Bortezomib (Velcade®), a proteasome inhibitor, is approved by the FDA for the treatment of multiple myeloma (MM). While effective, its use has been hampered by peripheral neurotoxicity of unexplained etiology. Since proteasome inhibitors alter protein degradation, we speculated that proteins regulating microtubule (MT) stability may be affected after treatment and examined MT polymerization in cells by comparing the distribution of tubulin between polymerized (P) and soluble (S) fractions. We observed increased MT polymerization following treatment of SY5Y and KCNR [neuroblastoma], HCN2, and 8226 [MM] cells, using five proteasome inhibitors; the baseline proportion of total α-tubulin in ‘P’ fractions ranged from ~41-68%, and increased to ~55-99% after treatment. Increased acetylated α-tubulin, a post-translational marker of stabilized MTs, was observed in the neural cell lines HCN1A and HCN2 and this was sustained up to 144 hours after the proteasome inhibitor was removed. Cell cycle analysis of three cell lines after treatment, showed ~50-75% increases in the G2M phase. Immunofluorescent localization studies of proteasome inhibitor treated cells did not reveal microtubule bundles in contrast to paclitaxel treated, suggesting MT stabilization via a mechanism other than direct drug binding. We examined the levels of microtubule associated proteins and observed a 1.4-3.7 fold increase in the microtubule associated protein MAP2, in HCN2 cells following treatment with proteasome inhibitors. These data provide a plausible explanation for the neurotoxicity observed clinically and raise the possibility that microtubule stabilization contributes to cytotoxicity.

Open Access Article

Stress-dependent changes in the properties of p53 complexes by the alternative translation product p53/47

Darren J. Powell, Roman Hrstka, Marco Candeias, Karima Bourougaa, Borek Vojteseka and Robin Fåhraeus
Pages 950 - 959
http://dx.doi.org/10.4161/cc.7.7.5626
Abstract | PDF

P53 plays a key role in the cellular response to damage exposure and in preventing the development of human cancers. Activation of p53 results in changes in the expression of a large number of gene products. However, relatively little is still known how p53 activation differentiates between different types of damages in different types of tissues or how this triggers either an apoptotic response or cell cycle arrest and DNA repair. The p53 message is translated into two products with distinct activities and stabilities through alternative mechanisms of initiation. P53/47 is initiated 40 codons down stream of the full length p53 and does not include the binding site for the E3 ubiquitin ligase Mdm2 or the transactivation domain I but retains the capacity to form p53 hetero- and homo-oligomers. Here we report that p53/47 controls the folding, the oligomerisation and the post-translational modification of p53 complexes and that it diversifies p53 properties in a cell stress-dependent fashion. P21 expression, for example, is under normal conditions not affected by p53/47 but is induced 18-fold after treatment of cells with the DNA damaging drug doxorubicin. This is accompanied by the recruitment of p53/47 to the p21 promoter.